De novo expression of macrophage migration inhibitory factor in atherogenesis in rabbits

Macrophage migration inhibitory factor (MIF) has been shown to play an impo rtant role in macrophage-mediated diseases. We investigate the potential ro le of MIF in atherogenesis using a hypercholesterolemic rabbit model. New Z ealand White rabbits fed with a 2% cholesterol diet developed hypercholeste rolemia and early fatty streaks at 1 month. The lesions became advanced at 3 months and were associated with de novo MIF expression by vascular endoth elial cells (VECs) and smooth muscle cells (SMCs), as demonstrated by immun ohistochemistry, reverse transcriptase-polymerase chain reaction, and in si tu hybridization. By contrast, there was no increase in MIF levels in rabbi ts fed a normal diet. In early atherogenesis, marked upregulation of MIF mR NA and protein by VECs and some intimal cells were closely associated with CD68(+) monocyte adhesion onto and subsequent migration into subendothelial space. Of significance, the accumulation of macrophages was exclusively lo calized to areas of strong MIF expression, which may be associated with the macrophage-rich fatty streak lesion formation. Upregulation of MIF by SMCs is transient during atherogenesis. Importantly, strong MIF expression by a ctivated macrophages may be responsible for the development of foam cell-ri ch lesions. Finally, the ability of MIF to induce intercellular adhesion mo lecule-1 expression by VECs implicates its pathogenic role in atherogenesis . In conclusion, the present study provides the first demonstration that MI F is markedly upregulated during atherogenesis, Upregulation of MIF by VECs and SMCs may play a role in macrophage adhesion, transendothelial migratio n, accumulation, and, importantly, transformation into foam cells. Furtherm ore, strong MIF expression by macrophages may both initiate and amplify the atherogenesis process.